1. Field of the Invention
The invention relates to saccharin derivatives which inhibit the enzymatic activity of proteolytic enzymes, to processes for preparation thereof, to method of use thereof in treatment of degenerative diseases and to pharmaceutical compositions thereof.
2. Information Disclosure Statement
Inhibitors of proteolytic enzymes are useful in treatment in degenerative disorders such as emphysema, rheumatoid arthritis and pancreatitis in which proteolysis is a substantive element. Serine proteases are the most widely distributed class of proteolytic enzymes. Some serine proteases are characterized as chymotrypsin-like or elastase-like based upon their substrate specificity. Chymotrypsin and chymotrypsin-like enzymes normally cleave a peptide bond in a protein at a site at which the amino acid on the carbonyl side is Trp, Tyr, Phe, Met, Leu or other amino acid which contains an aromatic or a large alkyl side chain. Elastase and elastase-like enzymes normally cleave a peptide bond at a site at which the amino acid residue on the carbonyl side of the bond is Ala, Val, Ser, Leu or other small amino acid. Both chrmotrypsin-like and elastase-like enzymes are found in leukocytes, mast cells and pancreatic juice in higher organisms, and are secreted by many types of bacteria, yeast and parasites.
Mulvey et al. U.S. Pat. No. 4,195,023 issued Mar. 25, 1980 describes methods of inhibiting elastase and treating emphysema with 4, 5, 6 or 7-R.sub.1 -2-R.sub.2 CO-1,2-benzisothiazolinone-1,1-dioxide (4, 5, 6 or 7-R.sub.1 -2-R.sub.2 CO-saccharin) wherein R.sub.1 is halogen, alkoxy, alkylamino, dialkylamino, alkoxycarbonyl, amino, nitro or especially hydrogen and R.sub.2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halophenyl, heteroaryl or substituted heteroaryl, for example 2-(2-furoyl)saccharin, and pharmaceutical compositions thereof.
Chen U.S. Pat. No. 4,263,393 issued Apr. 21, 1981 describes 2-aroylmethylsaccharins substituted or unsubstituted on aroyl and on the saccharin nucleus including for example as compound 12 2-[(p-fluorobenzoyl)methyl]saccharin as being "useful in photographic elements, film units and processes to provide electrons to immobile compounds which must accept at least one electron before releasing a diffusible dye or photographic reagent."
Jones et al U.S. Pat. No. 4,276,298 issued Jun. 30, 1981 describes 2-R-1,2-benzisothiazolinone-1,1-dioxides (2-R-saccharin) wherein R is phenyl or pyridyl substituted by from one to five of fluoro, nitro except mononitro when R is phenyl, trifluoromethyl, cyano, alkoxycarbonyl, alkylcarbonyl, carboxyl, carbamoyl, alkylacylamino, alkylsulfonyl, N,N-dialkylsulfamyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl and trifluoromethylsulfinyl "useful in methods of inhibiting proteases, especially elastase, and of treating emphysema rheumatoid arthritis, and other inflammatory diseases."
Reczek et al. U.S. Pat. No. 4,350,752 issued Sep. 21, 1982 describes 2-(heterocyclymethyl)saccharins substituted for unsubstituted on heterocyclyl and on the saccharin nucleus including for example as compound 28 2-[(1-phenyltetrazol-5-yl)thiomethyl]saccharin as "blocked photographic reagents . . . useful in photographic elements, film units and processes."
Dunlap et al. PCT Application WO 90/13549 published Nov. 15, 1990 describes saccharin derivatives useful as proteolytic enzyme inhibitors having the structural formula: ##STR2## wherein: L is --O--, --S--, --SO-- or --SO.sub.2 --;
m and n are each independently 0 or 1; PA1 R.sub.1 is halogen, lower-alkanoyl, 1-oxo-phenalkenyl, phenyl (or phenyl substituted by halogen, lower-alkyl, lower-alkoxy, nitro, amino, lower-alkylamino or di-lower-alkyl-amino) or heterocyclyl selected from 1H-(5-tetrazolyl), 5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl (when R.sub.2 as defined hereinbelow is other than phenylthio), pyrimidinyl, 2-benzoxazolyl, 2-enzothiazolyl, 2-phthalimidyl, 2-(1,3,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl), 5-thioxo-3-(1,2,4-thiadiazolyl), 4-(5-oxo-1,3,4-thiadiazolyl), 4-5-thioxo- 1,3,4-thiadiazolyl), 3-(1,2,4-thiazolyl), 4-(1,2,4-triazolyl), (1,2,3-triazolyl), 2-imidazolyl or 3-(1,2,4-triazolo[4,3-a]pyridinyl), or such heterocyclyl groups substituted on any available nitrogen atom by lower-alkyl, hydroxy-lower-alkyl, cycloalkyl, 2-, 3- or 4-pyridinyl, carboxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl, aminocarbonyl-lower-alkyl, lower-alkylaminmocarbonyl-lower-alkyl, di-lower-alkylamino-carbonyl-lower-alkyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower alkylamino-lower-alkyl, 4-morpholinyl-lower-alkyl, 1-piperidinyl-lower-alkyl, 1-pyrrolidinyl-lower-alkyl or phenyl (or phenyl substituted by amino, lower-alkyl-amino, di-lower-alkylamino, lower-alkanamido, N-lower-alkyl-lower-alkanamido, carboxy-lower-alkanamido, carboxy, carbo-lower-alkoxy, lower-alkoxy or halogen), or such heterocyclyl groups substituted on any available carbon atom by nitro, lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino, cycloalkylamino, mercapto, lower-alkylthio, amino-lower-alkylthio, lower-alkylamino-lower-alkylthio, di-lower-alkyl-amino-lower-alkylthio, 4-morpholinyl-lower-alkylthio, 1-piperidinyl-lower-alkylthio, 1-pyrrolidinyl-lower-alkylthio, carbo-lower-alkoxy or phenyl (or phenyl substituted by amino, lower-alkylamino, di-lower-alkylamino, lower-alkanamido, N-lower-alkyl-lower-alkanamido, lower-alkyl, lower-alkoxy or halogen); PA1 R.sub.2 is hydrogen, carbo-lower-alkoxy, phenyl or phenylthio; PA1 R.sub.3 is hydrogen, halogen, primary or secondary lower-alkyl, lower-alkoxy, carbo-lower-alkoxy, phenyl, fluoro-lower-alkyl, lower-alkenyl or cyano; PA1 R.sub.4 is hydrogen or from one to two substituents selected from halogen, cyano, nitro, amino, lower-alkanamido, phenyl-lower-alkanamido, diphenyl-lower-alkanamido, lower-alkylsulfonylamino, polyfluoro-lower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyhalo-lower-alkyl, cycloalkyl, polyhalo-lower-alkoxy, hydroxy, lower-alkoxy, carboxy, hydroxymethyl, formyl, aminomethyl, lower-alkylsulfonyl, polyhalo-lower-alkylsulfonyl, lower-alkylsulfonyl-aminosulfonyl and lower-alkoxypoly-lower-alkyleneoxy; and wherein the --CHR.sub.2 -- group is always appended either to a hetero atom of the L moiety as defined above or it is appended to a hetero atom of the R.sub.1 moiety, with the provisos that (i) when m and n are 0 and R.sub.2, R.sub.3 and R.sub.4 are all hydrogen, R.sub.1 cannot be halogen; (ii) when m is 0, n is 1, L is-S- and R.sub.2, R.sub.3 and R.sub.4 are each hydrogen, R.sub.1 cannot be 1-phenyl-1H-(5-tetrazolyl); (iii) when m is 0, n is 1, L is --O-- or --S-- and R.sub.2, R.sub.3 and R.sub.4 are all hydrogen, R.sub.1 cannot be lower-alkanoyl; (iv) when m is 0, n is 1, L is --O--, --S-- or --SO--, and R.sub.2 , R.sub.3 and R.sub.4 are all hydrogen, or when m is O, n is 1, L is --S--, R.sub.2 and R.sub.4 are hydrogen and R.sub.3 is halogen, or when m is O, n is 1, L is --SO-- or --SO.sub.2 --, R.sub.2 is carbo-lower-alkoxy and R.sub.3 and R.sub.4 are both hydrogen, R.sub.1 cannot be phenyl or substituted phenyl. PA1 L--R.sup.1 is a leaving group, H--L--R.sup.1 is the conjugate acid thereof and, when L is N, H--L--R.sup.1 has a pK.sub.a value less than or equal to 6, when L is O, H--L--R.sup.1 has a pK.sub.a value less than or equal to to 8, and when L is SO.sub.n, H--L--R.sup.1 has a pK.sub.a value less than or equal to 5; PA1 R.sup.2 is primary or secondary alkyl of two to four carbon atoms, primary alkylamino of one to three carbon atoms, primary alkylmethylamino of two to four carbon atoms, diethylamino or primary alkoxy of one to three carbon atoms; and PA1 R.sup.3 is from one to three substituents at any or all of the 5-, 6- and 7-positions and is selected from the group consisting of hydrogen, lower-alkyl, cycloalkyl, amino-lower-alkyl, lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, perfluoro-lower-alkyl, perchloro-lower-alkyl, formyl, cyano, carboxy, aminocarbonyl, R-oxycarbonyl, B.dbd.N wherein B.dbd.N is amino, lower alkylamino, di-lower-alkylamino, carboxy-lower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-azetidinyl, 4-morpholinyl, 1-piperazinyl, 4-lower-alkyl-1-piperazinyl, 4-benzyl-1-piperazinyl or 1-imidazolyl, 1-lower-alkyl-2-pyrrolyl, lower-alkylsulfonylamino, perfluoro-lower-alkylsulfonylamino, perchloro-lower-alkylsulfonylamino, nitro, hydroxy, lower-alkoxy, cycloalkoxy, B.dbd.N-lower-alkoxy, hydroxy-lower-alkoxy, poly-lower-alkoxy-lower-alkoxy, hydroxy-poly-alkylenoxy, lower-alkoxy-poly-lower-alkylenoxy, B.dbd.N-carbonyloxy, carboxy-lower-alkoxy, R-oxycarbonyl-lower-alkoxy, methylenedioxy, di-lower-alkylphosphonyloxy, R-thio, R-sulfinyl, R-sulfonyl, perfluoro-lower-alkylsulfonyl, perchloro-lower-alkylsulfonyl, aminosulfonyl, lower-alkylaminosulfonyl, di-lower-alkylaminosulfonyl and halo wherein R is lower-alkyl, phenyl, benzyl or naphthyl or phenyl or naphthyl having one or two substituents selected from the group consisting of lower-alkyl, lower-alkoxy and halo; PA1 or a pharmaceutically acceptable acid addition salt thereof if the compound has a basic functional group or a pharmaceutically acceptable base addition salt thereof if the compound has an acidic functional group.